JPS59206382A - Ergoline derivatives and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides ergoline derivatives having the general formula I. Here, R1 in the above formula I is a hydrogen atom or a methyl group υ, R2
is hydrogen atom, norogen atom, methyl, cyano, 01~
C4 alkylthio or phenylthio group V), Ry
and R8 is a hydrogen atom and R3 is a hydrogen atom or a methoxy group, or R7 is a hydrogen atom and R3
and R8 together represent a bond, or R3
is a hydrogen atom or a nodoxy group, R7 and R8 together represent a bond, R4 is a hydrocarbon group having 1 to 4 carbon atoms, and R5 is a hydrogen atom,
is a hydrocarbon group having 1 to 4 carbon atoms or is a phenyl group, X is an oxygen atom, a sulfur atom or an imino group, R9 is a hydrogen atom, and B is cyano, C2
~C5 alkoxycarbonyl or carbamoyl group, or R9 and B together represent a 10- (wherein W is an oxygen atom or an imino group) group, and A is of the formula 0HR6% 0H2-OHR6 or 0H =CR6(
In these formulas, R6 represents a hydrogen atom or a 01-C4 alkyl group, and n is 0, 1 or 2.
It is.

Pharmaceutically acceptable salts of these ergoline conductors are encompassed by the present invention.

In the definition of R2, the term "halogen" is preferably to be understood as including chlorine and odorous atoms; nevertheless, the term "halogen" also includes fluorine atoms. In the definitions of R4 and R5, hydrocarbon groups bearing 1 to 4 carbon atoms are intended to include alkyl, cycloalkyl and unsaturated (both ethylenic and acetylenic) groups. Typical groups include methyl, ethyl, n-propyl, isopropyl, butyl, t
-butyl, inbutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

"Pharmaceutically acceptable salts" include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid;
M units such as malonic acid, co/\phosphoric acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mantelic acid, methanesulfonic acid, ethanesulfonic acid, p-)luenesulfonic acid or salicylic acid. Salts formed with acids that retain all of the bioavailability and properties of the free base and are not biologically or otherwise undesirable are referred to.

Substituents R1+R2+R3+R7tR8 and R5 are preferably hydrogen atoms. Preferably R4 is methyl, n is 1 and B and R9 together represent a -C- group. Preferably W and X are oxygen atoms and A represents a group having the formula -CH2- or -0H2-CH2-, most preferably A is a group having the formula -0H2-.

The present invention also provides an erucorin derivative having the formula ■ (wherein R1rR2+R3+R4+R7+R8+AeB and n are as defined above); The present invention also provides a method for producing the compound of the formula (2), which includes the step of condensing with a compound that produces

The resulting compound of formula I (wherein R9 is a hydrogen atom) can be converted by cyclization to another compound of formula I (wherein R9 and B are taken together to represent a -C=W group, where W- is as defined above).

The entanglement step can be carried out in a medium such as water, ethanol, acetic acid or pyridine at a temperature of 50 to 100 DEG C. with or without the addition of an acid such as hydrogen chloride.

The cyclization can be carried out in the same condensation medium or with M7L separated from the formula I (
In the formula, R9 is hydrogen) under vacuum to 160-1
This can be carried out by heating to 60°C. Once the reaction is complete, the crude product can be purified by crystallization or chromatography.

The ergoline derivatives of general formula (2) which are the starting materials for the process of the invention are known compounds or can be prepared by established methods starting from known compounds. According to one preferred method, a compound having the general formula (1) in which A is a -CH2-CHR6 group is prepared by converting a suitable ergoline primary amine to a compound of the formula 0H2=O-B (wherein R6 and B are as defined above). It is obtained by reacting with 4 acrylic materials (which are as follows). Alternatively, the formula Br(OH2)
A compound having nl-OH-B (wherein R6 and B are as defined above and m is 0 or 1) is reacted with a suitable ergoline primary amine to form the general formula
It can be made into a compound having the following.

The compound of formula (1), which is another starting material for the process of the invention, is a known compound and can be prepared in situ by reacting the appropriate compound with an acid such as hydrochloric acid.

The free ring form of a compound of formula I can be converted into the silica addition salt form and vice versa in conventional manner.

The compounds according to the invention and their pharmaceutically acceptable salts exhibit pharmacological activity.

For example, they exhibit prolactin α-inhibitory effects as shown by inhibition of fertilized egg implantation in the uterus on the fifth day after fertilization in female rats [E.

F1uckiger and others% “HANDB, FiXP
PHARMAO, JgJ Volume 49, Page 615 (197B
2007)].

In particular, the compounds of the invention and their salts are active as antihypertensive agents.

Indirect measurement of systolic blood pressure is possible using Charles River (C!
Groups of four acutely hypertensive rats (hereinafter abbreviated as SHR) of the 8- to 10-week-old strain Rlver were kept in an environment at 36°C for 10 to 15 minutes to record the pulse pressure. Next, using a W1W% BP recorder, model 8005, the total blood pressure and six strokes were measured by the indirect tail cuff method.

The test compound was suspended in 5% gum arabic in a series of 4
Oral administration was once daily for 2 days and measurements were performed before the start of treatment and 1 and 5 hours after dosing on days 1 and 4 of treatment. Dosages are for free base. Control animals received vehicle only (0,2 Ine/100' body weight)k
Given the.

As a reference standard, hydralazine (1-5 mg/k
y, oral) and α-methyldopa (60-100 m1
? /string, oral) was also tested. Drug-induced changes in systolic blood pressure and VC were calculated as the difference from pre-treatment values and reported as the average of 4 rats.

Tables 1 and 2 show the results for compounds of the invention, along with data for all control vehicles and two reference standards, hydralazine and α-methyldone.

Systolic depression (hereinafter abbreviated as l8BPj) and 6
The HRJ (hereinafter abbreviated as "HRJ") remained stable throughout the experimental period in vehicle-treated rats; on the other hand, all of the compounds of the invention were administered orally at 1-2 C11.
It was very effective in lowering SEP 'ii in the dose range of g/kP. This effect was due to the fact that there was no overall reflex increase in HR, whereas a moderate decrease in HR was observed for the same compound.

The antihypertensive effect of all compounds began immediately and remained very pronounced during the entire experimental period. These effects are the first
The results were similar on day 4 and month 4, indicating that hypertolerance does not occur with the compounds of the present invention. In particular, both the compounds prepared in Examples 1 and 3 showed very pronounced and long-lasting effects without substantially changing the HR.

Example 4.5.8.9.12.16. when compared to the reference standard.
Compounds described in 16.19.26.24 and 28 [tested at dosages 1 to 7.5 m9/kl (oral)]
] was administered with hydralazine (1-5 my/ky % orally) and α-methyldopa (30-100 mL/ki,
It has been shown how these latter drugs are more effective without inducing the reflex increase in HR observed when administered orally.

The following Table 1 shows the systolic blood pressure (SE
The effect of the test compound on P) is reported as the mean difference from the pre-treatment value (mmj (g) (94 rats per group) and in Table 2 the 6-stroke frequency (HR )
The effect of the test compound on the test compound is reported as the average difference from the previous value (7 minutes of pulsation) (4 rats per group).

Table 1 Changes in SEP (Graph Hg) Vehicle - +2.5 -7.5 -6.4 -
5.0 Example 1 Gug production 20 -90.0 -62.5
-62.5 -46.2 Example 3 // 20
-60.0 -725 -90.0 -62.5 Example 4
// 20 -56.5 -45.0 -42
．． 5 -50.0" // 5 -35
．． 0 -40.0 -43.7 -45.0 Example 5
// 7.5-55.0 -56. '2 -5
5.0 -53.7 Example 8 // 20 -30
．． 0 -10.0 -56.2 -37.5f119
// 7.5-51.2 -65.0 -
82.5 -55.0 Example 12 // 7.5
-52.5 -38.7 -67.5 -41.2 Example 1
3 // 7.5-37.5 -26.2
-50.0 -31゜7 cases 16 〃1 -20.0
-28.7 -46.7 -52.5 Example 19 //
15 -50.0 -33.7 -62.5 -
26.7 Example 25 // 20 -51.2 -
60.0 -85.0 -72.5 Example 24 1/
5 -38.7 -66.7 -41.7 -5B
, 5 cases 28 // 1 -27.5 -31
．． 2-70. [ ] -30,0 hydralazine
1 -5.1 -15.7 -5.0 -Q, 3"
5 -40.2 -20.0 -20.4
-7.0"-Methyl do'ゞ 30 -10.4
-20.1 -to, o +, o, 5. ．． .

“ 100 -10.[] -25,4-2
0,2-25,0 Table 2 Change in HR (7 minutes of beating) Vehicle - -5,0+12.0 -10.0 -
19.0 Example 1 production 20 +4.0 -4
0.0 -33.0 -8.0 Example 5 // 2
0 -20 -10.0 -25.0 -7.0 Example 4
// 20 +13.0 +23.0
-11.0 -40.0// // 5
-15.0 -3Q, 0 -40.0 -23.0 Example 5
// 7.5 -67.0 -20.0
-42.0 -10.0 Example 8 // 20
-13.0 +0.4 +40.0 -20
．． 0 case 9 // 7.5 -60.0 -32
．． 0 -75.0 -28.0 Example 12//7
．． 5 -40.0 -2aO+8.0 +2.0Example 1
3 // 7.5 +13.0 -55.0
+37.0 -20.0 Example 16 // 1
-2aO-8, 0-60, 0-35, 0 example 19 //
15 -18.0 -32.0 -35.0
+15.0 example 25u 20 -aO+1
7 +42.0 -18.0 Example 24 //
,,, 5 -23.0 +17. Q
+30.0 -27.0 Example 28 // 1
-13.0 -23. Q +15.0 -15
．． 0 hydralazine 1+30.0 +35.0
+25.0 +15. Ott 5
+40.0 +45. Q 10 is, o'
+15.0α-methyldopa 30 +65.
0 +40.0 +45.0 +30.0〃1
00 +70.0 +40.0 +5L1.
0 +IL1.0 The present invention further encompasses pharmaceutical compositions containing a therapeutically effective amount of a compound having Formula 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. It is something to do.

Administration of Compounds I and their non-toxic pharmaceutically acceptable acid addition salts or mixtures thereof may be parenterally or orally, preferably orally.

As used herein, the term "therapeutically effective amount" includes that amount that produces the desired effect without causing adverse side effects. However, the effective dosage is 9.
Approximately o,ooi ~ 0.5 mfl/kg preferably 0.
01 to 0.251 + 1 g/kP''r16°Pharmaceutical carriers typically employed with the compounds of this invention can be solid or liquid and are generally selected depending on the intended method of administration. Thus, for example, solid carriers include milk/sugar, sucrose, gelatin, agar, and the like, while liquid carriers include water, syrup, peanut oil, olive oil, and the like.

The combination of the selected compound and carrier can be prepared into a number of acceptable forms such as tablets, capsules, balms, solutions, emulsions, powders and syrups.

The present invention will be explained below by way of example.

Example 1 6-Methyl-8β-CC1H,5H)-2,4-dioquine-dihydro-1-pyrimidinylmethyl]-ergoly
(I: R1=R2=R3=R7=RB=H%
R4=OH3, n=1-A=an2caR
6, R6=H%B and R9=-0=W %W=X=O
%R5-H] 5, 11 in 100 methanol
A mixture of 8β-aminomethyl-6-methyl-ergoline and 1.8-methyl acrylate was refluxed for 4 hours. The solvent is evaporated under reduced pressure and the residue is crystallized from diethyl ether to give 6-methyl-8β-(N-(2-methoxycarbonylethyl)-aminomethylcouergoline), which melts at 130-132°C. ...: R1=R
2=R3=,=R7=R8-Hs R4=O)T3,
n=1% A=C! H2-0HR6, R6=H, B
-0000H3) was obtained by adding a solution of potassium cyanate at 2,86F in 60g water to 120d water and 35rn1. A solution of 6 g of 6-methyl-8β-CM-C2-methoxycarbonylethyl)-aminomethylcouergoline in 1N hydrochloric acid was prepared. The reaction mixture was heated at 80° C. for 4 hours and left at tail temperature overnight. The solid precipitated out completely and was then recrystallized from ethanol to give the title compound 4,5f melting at 330 DEG C. with %A.

Example 2 6-methyl-8β-(N-(2-methoxycarbonylx
f)-N-carbamoylaminomethyl]--ergoline (1: R1=R2=R3=R5=H% R4=OH
5, n-1, A=OH20HR6, R6=11, X
=O, B=(1!OOC!H3, R7-R8=R9-H
] 8,5 in 120 ml of water and 35 d of 1N hydrochloric acid
2 of 6-methyl-8β-(N-(2-methoxycarbonyl-ethyl)aminomethylcouergoline (1:R1=
R2=R4=H% R4=OH5, n-1, A=OH2
-0HR6, R6""H, B=OOOOOH! , ,Example 1
A mixture of potassium cyanide (prepared as described in ) and 2.86 F potassium cyanide was heated at 60° C. for 1 hour. This solution was then neutralized with 1ffi 1N sodium hydroxide and extracted with chloroform. The M nuclear layer was completely evaporated and the residue was purified by column chromatography on silica gel to give the title fraction of 6.5 F.

Ethyl acetate/dimethylformamide/n-butanol/
Rf in pilin (4:3:3:1 volume ratio) =
0.45゜MSCF, D, ): 384 (M+),
552 (M+-0H30H).

Example 3 6-Methyl-8β-(2,4-dioxo-1-imidazolidinyl-methyl)-ergoline (I: R1=R2=
R5=Hs R4=OHs, n=1, A=OHR6
, R6=H%Ry=RB=R5=H%B and R9=
-0=W%W=X=O) 601d solution of ethyl 1,3-bromoacetate in dimethylformamide total 90
8β- of 62 in dimethylformamide of yd
Added to warmed solution of aminomethyl-6-methyl-ergoline. Upon completion of the reaction, the solution was reduced in volume by evaporation under vacuum, poured into ice-cold water, and extracted with chloroform.

The machine was removed in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate/methanol (9:1 volume ratio) as eluent.

(N-ethoxycarbonylmethyl-aminomethyl)-ergoline (1: R1=R2=R3=H%R4=CH3
, n=i, A-CHR6, R,5=H%B=co2
c2a5) was obtained.

6.5 g of 6-methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ercoline was treated with 1.75 F potassium cyanogen as described in Example 1 and the title compound (melting point >600 ℃) was obtained in 72% yield.

Example 4 6-Methyl-8β-(N-(2-methoxycarbonylethyl)-N-methylcal/<moylaminomethyltoergoline [l: R1=1 2-R3=H, R4-aH3
, n”'1 , A=C!H20HR6, R6=R7=R
B=Rq=H%R570H3, B=0000H3, X=
O] 8,51 6-methyl- in 100 pyridine
A mixture of 8β-(N-(2-methoxycarbonylethyl)-aminomethylcuergoline (prepared as described in Example 1) and 2.95-incyan Yi-methyl was heated at 60°C for a total of 1 hour. After completely evaporating the solvent, the residue was crystallized from methanol and the melting point was 140-142°C.
The title compound No. 8,51 was obtained.

Example 5 6-Methyl-8β-(:(tH,3H)-2,4-dioxo-6-methyl-dihydro-1-pyrimidinyl-methylsiergoline (1:R1=R2=R3=H%R4=
C! H3, n=1, A=OH20HR6, R6=H,
B and R9--0=W %R5-CH! , ,R7=
R9=H, X=W=O]6-methyl-8β-(N-(2
-Methoxycarbonylethyl)-N-methylcarbamoyl-aminomethylcouergoline (prepared as described in Example 4) was heated in vacuo at 145°C for 1 hour to determine the melting point after crystallization from methanol. is 118~12
The title compound of 6,51 was obtained at 0°C.

Example 6 Low methyl-8β-(N-ethoxycarbonylmethyl-
N-methylcarbamoylaminomethyl)-ergoline (
1: R1=R2=R3=H1R4=OJ, n=1
s A=OHR6% R6=R7=RB=Rq=H%
R5=OH3, B=OO0,02H5,X-0] 6-methyl-8β-[:N-(2-methoxycarbonylethyl)-aminomethylcouergoline instead of
Working as in Example 4 except using methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ercoline (prepared as described in Example 6), a melting point of 165
The title compound was obtained at ~167°C.

Example 7 Low methyl-8β-(2,4-dioxo-6-methyl-
1-imidazolidinylmethyl)-ergoline (1: R
1=R2=R3=H%R4=OH3, n=i, A=O
HR6, R6=R7=R8=H%R5=CH3, B and R9terC=W%W=X=O:+6-Methyl-8β-
(N-ethoxycarbonylmethyl-N-methylcarbamoyl-aminomethyl)-ergoline by heating in vacuo at 140°C for 1 hour with υ min %l FM
The compound having a temperature of 250° C. was obtained in 77% yield.

Example 8 6-Methyl-8β-[N-(2-methoxycarbonylethyl)-N-propylcarbamoyl-aminomethyltoergoline (1:R1=R2=R3=)i%R4=OH
5, R5=(3'H2C!H2C!H3, n=1, A
-OH20HR6, R6=R7=R8=R9=H%x=
o, B=cOOcH3:] The title compound was prepared as described in Example 4, except that propyl isocyanate was used instead of methyl isocyanate. The yield is 8
5% and the melting point was 130-162°C.

Example 9 6-Methyl-8β-((IH,3H)-2,4-dioxo-6-propyl-dihydro 1-pyrimidinyl-methyltoergoline (1: R1=R2=R3=H% R
470H5, n=1, A=CH20HR6, R6
=R7=RB=H% R5=OH20H2C! H5B and R9=-〇=W%X=W=O)6-methyl-8β-
(6-methyl-8β-(N-(2-methoxycarbonylethyl)-N-propylcarbamoyl-aminomethyl Working as in Example 5, except using twoergoline (prepared as in Example 8), the title compound with a melting point of 201-202<0>C was obtained in 70% overall yield.

Example 1Q 6-Methyl-8β-(N-(2-methoxycarbonylethyl)-N-isopropylcarbamoyl-aminomethyltwoergoline (1: R1=R2=R3=H1R4=
C! H3s n= 1, A=OH20HR6s R5
=CH(OH5)2, R6=R7=R9=R9=H
%B=0000J, X=O) The title compound having a melting point of 112 DEG-115 DEG C. was obtained by proceeding as in Example 4, except that inpropyl isocyanate was used in place of methyl isocyanate.

Example 11 6-Methyl-8β-[(IH,3H)-2,4-dioxo-6-inzolovyl-dihydro-1-pyrimidinyl-
Methyl two ergoline (I:R,=R2=R3=H,
R4=CH3, n=1, A=OH20HR6, R6=
R7=RB=, H%R5=CH (part 3)! , B and R
9=-0=W, X=W=O)6-methyl-8β-(
N-(2-methoxycarbonylethyl)-N-isopropylcarbamoyl-aminomethyltwoergoline (Example 1
The title compound (prepared as described above) was prepared by heating at 150°C for 2 hours (melting point 175-177°C).
) was obtained with an overall yield of 60%.

Example 12 6-methyl-8β-[N-ethoxycarbonylmethyl-
N-propylcarbamoyl-aminomethyltwoergoline (1: Rt = R2 = R3 = H% R4 = OH3, R
5=C! H2C! H20H3s n=i, A=OH
R6, R6=R7=RB=Rq=H,X;0%B=OO
OOH20H3] Proceed as in Example B except that propyl isocyanate is used in place of methyl isocyanate to obtain a melting point of 109 to 1.
The title compound at 10° C. was obtained in 80% yield.

Example 13 6-Methyl-8β-(2,4-dioxo-6-broby-1-imidazolidinyl-methyl)-ergo',Jn(1:R1=R2=R4=H%R4=CH5, n=1
, A=CHR6, R6=R,=R8=H, R5=OH2
0H20H3, B O, ]:biR9=-C=W.

X=W=O] The melting point of 6-methyl-8β-[N-ethoxycarbonylmethyl-N-70 vincarbamoyl-aminomethylcouergolinkara prepared in Example 12 by heating in vacuum at 140°C for 1 hour The title compound having a temperature of 188-190°C was obtained in 68% yield.

Example 14 6-/T/I, -8β-(N-ethoxycarbonylmethyl-N-isopropylcarbamoyl-aminomethyl)-
Ergoline 0: R1=R2=R5=H, R4=OE5
, n=1, A=OHR6, R6=R7=R8=R9
=H, R5=CB(CH3)2, B-00002H5,
X=0,1 The melting point is 118~1 by operating as in Example B except using isopropyl isocyanate instead of methyl isocyanate.
The title compound, 120C, was obtained.

Example 15 6-Methyl-8β-(2,4-dioxo-6-isoprobyl-1-imidazolidinylmethyl)-ergorif 1
:l :R1=R2=R3-'H, R4=OH3, n=
1, A--6, R6=R7=RB=H, R5=(3
H(CH3)2 s B and R9=-c-w%X=W
=O] 6-methyl-8β-(N-ethoxycarbonylmethyl-
Starting from N-isozolobylcarbamoyl-aminomethyl)-ergoline (prepared as in Example 14), the title compound (melting point 210-212°C) was prepared by heating in vacuo at 160°C for 2 hours. Obtained in 75% yield.

Example 16 Low methyl-8β-(2-[(1u,6u)-2,4-
dioxo-dihydro-1-pyrimidinyl]-ethyl)-
Ergoli 7 [1: R1-R2=R5=H, R4-J
3H54n=2% A=OH2C! HR6, R5=R
4=R,=R8=H%B and R9=-0=W, W
=X=O:) Proceed as in Example 1 except for using 8β-aminoethyl-6-methyl-er5-phosphorus instead of 8β-aminomethyl-6-methyl-ercholine until the melting point is 140-142°C.
The title compound was obtained in 74% yield.

Example 17 Low methyl-8β-C2-<2.4-dioxo-1-
imidazolidinyl)-ethyl]-eryoline (1:R
1=R2=R1,=H%R4=OH3,n-2,A=O
HR6, R5=R6=R7=R8=H, E and R9=
-0=W% The title compound at 244° C. was obtained in 68% yield.

Example 18 6-Methyl 8β-((IH,3H)-2,4-dioquine-dihydro-1-pyrimidinyltwoergoline-(
1: R1=R2=R3=H%R4=OH3, n=o
, A=OH20HR6% R5=R6=R7=RB=H
% E and R9=-0==W, X=W=O:)8
The title compound having a melting point of 612-314° C. was prepared by proceeding as in Example 1, but using 8β-amino-6-methyl-ergoline in place of β-aminomethyl-6-methyl-ergoline. 79% yield.

Example 19 6-Methyl-8β-(2,4-dioxo-1-imidazolidinyl)-ergo'line [R1=R2=R3=H.

R4=C! H3, n-0% A=CHR4, R5=R6=
R7=RB=Hs B and R9 me C=W%X=W≧
0] The above title compound having a melting point of 295-297° C. was prepared as in Example 6, except that 8β-amino-6-methyl-ergoline was used in place of 8β-aminomethyl-6-methyl-ergoline.゜Obtained from Kaijumine.

Example 20 1,6-dimethyl-8β-((1H,3H)-2,4-
Dioxo-dihydro-1-pyrimidinylmethyl couergoline (1:R2=Rg=Rs=R6=R7=Ra=H
% R1”R4=cH3゜n=1, A=CjH20H
R6s B and R9=-0=W %X=W=O:18
The procedure was as in Example 1, except that 8β-aminomethyl-1,6-dimethyl-ergoline was used instead of β-aminomethyl-6-methyl-ergoline, and the melting point was 614-31.
The title compound was obtained with 75% yield at 6°C.

Example 21 1,6-dimethyl-8β-(2,4-dioquine-1-imidazolidinyl-methyl)-ergoline [I:R2-R
3=R5=R, 5=R7=RB=T(, R1=R4=C
H5, n=1 4 A=(1'l yo 1 yo 6% B and R9=-U-w, x=w-o]8β-aminomethyl-
The title compound having a melting point of 292-294°C was obtained in 65% yield by proceeding as in Example 6, except that 8β-aminomethyl-1,6-dimethyl-ergoline was used in place of 6-methyl-ergoline. I got it.

Example 22 6-, methyl-10-methoxy-8β-(2,4-dioquine-1-imidazolidinylmethyl)-ergoline (1:R1=R2=R5-R6=x7-R8=lH
, R3-=-00H3, 1R4=aa3, n=1%
A=C! HR6, B and R9=-6=w %x=w
=o) Proceed as in Example 3, except that 8β-aminomethyl-6-methyl-10-methoxy-ergoline is used instead of 8β-aminomethyl-6-methyl-ergoline, with a melting point of 264-236°C. Total 68% of the above title compound
Obtained in yield.

Example 26 Rhomethyl-8β-CCIH,5H)-2,4-dioxo-1-pyrimidinyl-methylcouergoline [I:R
1=R2=R3=R5=R6=R7=RB=H, R4"
0OH3, n=1% A=OH=OR6, B and R9=-6=w, x=w=o)6-methyl-8β-(
Proceed as in Example 1, except using 6-methyl-8β-[(6-acrylic acid ethyl ester)-6-aminomethyltoergoline instead of N-(2-methoxycarbonylethyl)-aminomethyl-ergoline. Then m, p, >
The title compound at 320° C. was obtained in 48% yield.

Example 24 6-methyl-8β-((1'H)-2-thioquine-4
-Oxo-tetrahydro-1-pyrimidinylmethylcouergoline [1:R1=R2=R3=R5=RIS=R
7”R13=11%R4=CH3%n=1, A=OH
2CHR6, B and R9=-c=w, w-○, X=
S) Proceed as in Example 1, except using potassium thiocyanate instead of potassium cyanate, m, p, > 300°C
The title compound was obtained in 58% yield.

Example 25 6-methyl-8β-((1,H)-2-thioxo-4
-oxo-6-methyl-tetrahydro-1-pyrimidinyl-methylcouergoline CI: R1=R2-Rg=
R6=R7=RB=H% R4=R5=OH5, n=
1, A=OH20HR6, B and Rq""-0:W
%W-o, was obtained in 74% yield.

Example 26 6-n-propyl-8β-(:(1H)-2-thioxo-4-oxo-5-methyl-tetrahydro-1-pyrimidinyl-methyl]-ergoline CI: R1=R2=R
3=R6=R7=RB=H, R4=n-03H7, R5
=OH3, n=1.

A-OH2CHR6, B and R9--0=W %W=
O, Obtained in yield.

Example 27 Loaryru 8β-C(1H) -2-thioxo-4-
Oxo-6-methyl-tetrahydro-1-pyrimidinyl-methyltwoergoline (1: R1=R2 and R3-R
6=R7=R8=H%R4=7rill, R5-0H3,
n=1, A=cH20HR6゜B and R9===
-c-w %W myo% The compound was obtained in 77% yield.

Example 28 6-methyl-8β-(2-thioxo-4-oxo-6-
Methyl-1-imidazolidinylmethyl)-ergoline (
1: R1=R2=R5 R6=R7=RB=I(s
R4=R5=OH5, n=4% A=CHRd%
(B and
The title compound was obtained at 265° C. in 85% yield.

Example 29 6-broby-8β-(2-thioquine-4-oxo-5
-Mef-1-imidazolidinylmethyl)-ergoline (1:R1=R2=R5=R6=Ry=R8-Hs R
4=n-05H7, R5=OH5%n==1%A=O
HR6, Bk and R9=-0=w, w=o, x=s
) The title compound was prepared as Example 28, except that 8β-aminomethyl-6-propyl-ergoline was replaced by 8β-aminomethyl-6-methyl-ergoline.
Obtained in 8% yield.

Example 30 6-allyl-8β-(2-thioxo-4-oxo-6-
, methyl-1-imidazolidinyl-methyl)-ergoline [1:R1=R2=R5=R6=R7=R8'=H%
l'j4=allyl, R5=OH5, n=1, A=O
HR, S, B Oyobi R9 = -cPw.

W-O%
Obtained from the interest rate.

Example 61 6-methyl-8p-(N-(,2-cyanoethyl)-
N-carbamoyl-aminomethyl]-ergoline [
1: R1=R2''R3°R5=R6-R7=R8=R9
“H, R4<R3.

n-1, A”=OH2CiHR6s X2=O%B=C
[jN]Process as in Example 1 except for using acrylonitrile instead of methyl acrylate.
(N-(2-cyanoethyl)-aminomethyl]-ergoline (melting point 169-171°C) was obtained in 80% yield. From this, the title compound having a melting point of 252-254°C was obtained by working as in Example 2. I got it.

Example 32 6-methyl-8β-((IH,3H)-2-oxo-4
-imino-dihydro-1-pyrimidinyl-methyltwoergoline (1:R1=R2=R3=R5=R6=R7=
RB=H, R4=QH3% n=1, A=OH20H
R6, B and R9=-c=w, W=NH.

X=O) The compound prepared in Example 61 was heated in vacuo at 150°C for 1 hour to give the title compound with a melting point of 248-250°C in a total yield of 45%.

Example 66 2-bromo-6-methyl-8β-(2,4-dioxo-
1-imidazolidinyl-methyl)-ergoly 7
(1:R1=R4=R5=R6=R7""RB=H%
R2=Br% R4=OH4, n=i, A-O
HR6, E and R9=-C! =W, X=W=O)
The procedure of Example 6 was repeated except that 8β-aminomethyl-2-bromo-6-methyl-ergoline was used instead of 8β-aminomethyl-6-methyl-ergoline.
The title compound was obtained in 64% yield with a temperature of 9-281°C.

Example 64 2.6-dimethyl-8β-(2,4-dioquine-1-imidazolidinyl-methyl)-ercoline [I:R1-
R3=R5=R6=R7=RB=H, :R2=R4-O
H3% n=1, A=OHR, 5, B and R9=-
6=W, x-w=o) 8β-aminomethyl-2, instead of 8ρ-aminoethyl-6-methyl-ergoline
The title compound having a melting point of 215-217°C was obtained in 75% yield by operating as in Example 6 except using 6-dimefiv-ergoline.

Example 65 2-thiomethyl-6-methyl-8β-(2,4-dioxo-1-imidazolidinylmethyl)-ergoline [1:
R1=R3=R5=R, 5-R7=R8=H, R2=
SOH5, R4=OH3, n=1, A-OHR6, B and R9=-n=W %x=w-o) 8β-aminomethyl-2- instead of 8β-aminomethyl-6-methyl-ergoline The procedure was as in Example 6, except that thiomethyl-6-methyl-ergoline was used, and the melting point was 255-257°C.
The title compound was obtained in a yield of 62%.

Example 66 6-n-propyl-8β-(2,4-dioxo-1-imidazolidinyl-methyl)-ergoline [1: R1=
R2=R3=R5=R6=R7=RB=H%R4=n0
3 R7, n=1, A=C! HR6, B and R9=
-(:!=W%X=W=O)8β-aminomethyl-6-
8β-aminomethyl-6 instead of methyl-ergoline
Working as in Example 6 except using -n-propyl-ergoline, the title compound with a melting point of 168-170<0>C was obtained in 80% yield.

Example 67 6-Methyl-8α-(2,4-dioxo-1-imidazolidinyl-methyl)-ergoline [:l:R1=R2-
R5=R5=R6=R7=RB=H%R4=C! H5,
n=1% A=OHR6hBOyobiR9=-c=w
%x=wo) 8α-aminomethyl-6-methyl-instead of 8β-aminomethyl-6-methyl-ergoline
Working as in Example 6 except using ergoline, the title compound was obtained in 58% yield with a melting point of 199-201°C.

Example 68 6-Methyl-a -C[1H,,5u)-2,4-dioquine-dihydro-1-pyrimidinyl-methyl) -8,
9-ditehydroergoline (1: R1=R2=R5
=R5=R6=H, R4=OH5, R7 and R8=bond, n=i, A=CH2C'HR6, B and R9-C
-W,
, 9-ditehydroergoline was used as in Example 1 to obtain the title compound with a melting point of 190-192C in a total yield of 66%.

Example 39 6-Methyl-8-(2,4-dioxo-1-imidazolidinyl-methyl)-8,9-didehydro-ergoline (1: R1=R2-R3=R5=R6=H%R4=C
! H3% R7 and R8=% binding n=1 s k=
OHR6, B and R9=-0=W.

X=W=O) Proceed as in Example 6, except that 8-aminomethyl-6-methyl-8,9-didehydro-ergoline is used instead of 8β-aminomethyl-6-methyl-ergoline to obtain a melting point of 204 The title compound was obtained at ˜206° C. in 72% yield.

Example 40 6-Methyl-8β-[(1H,3H)-2,4-dioxo-dihydro-1-pyrimidinylmethyl) -'9.1
0-Didehydroergoline (1:R1R2=R5=
R6=R7=H.

R3 Oyobi R8 Goai, R4BOH3, Te1 % k=2
0H20HR6, B and R9=-'O=W, X=
W-0) 8β-aminomethyl-6-methyl-9,10 instead of 8β-aminomethyl-6-methyl-ergoline
Working as in Example 1 except using -didehydro-ergoline, the title compound having a melting point of 290-292°C was obtained in 77% yield.

Example 41 6-Methyl-8β-(2,4-dioquine-1-imidazolidinyl-methyl) -9,to-didehydro-ergoline CI: R1=R2==R5=R6=R,=f(
%R3 and R8=bond, R4-OH3, n-1, A#
CHR6% B and R9 = -0-W% Working as in Example 6, the title compound having a melting point of 282 DEG-284 DEG C. was obtained in a yield of 78%.

Continuation of page 1 Priority claim @ May 27, 1983 ■ United Kingdom (GB
) [Yes] 8314816 0 Inventor Ardemio Temperilli Via Aguissola, Milan, Italy 21 0 Inventor Patricia Salvati Via Aguissola, Milan, Italy 16

Claims (1)

[Claims] 1) A compound/product having the formula I or a pharmaceutically acceptable salt thereof [wherein R1 in the above formula I is a hydrogen atom or a methyl group, and R1 is a hydrogen atom or a methyl group;
2 is hydrogen atom, halogen atom, methyl, cyano, 01~
C4 alkylthio or phenylthio group'), Rv
and R8 is a hydrogen atom and R3 is a hydrogen atom or a methoxy group, or R7 is a hydrogen atom and R3
and R8 together represent a bond, or R3
is a hydrogen atom or a methoxy group, R7 and R8 together represent a bond, R4 is a hydrocarbon group having 1 to 4 carbon atoms, and R5 is a hydrogen atom,
is a hydrocarbon group having 1 to 4 carbon atoms or is a phenyl group, or is an oxygen atom, a sulfur atom or an imino group, R9 is a hydrogen atom and B is cyano, C2
~C5 alkoxycarbonyl or carbamoyl group, or R9 and or imino group), and A is 2〇HR6,0H2-OHR6 or 0H=O
represents a group having R6 (in this formula, R6 is a hydrogen atom or a C1-C4 alkyl group), and n is 0.1 or 2]. 2) R1 is a hydrogen atom. is a methyl group, -R2 is a hydrogen atom, bromine atom, methyl group, or thiomethyl group, R7 and R8 are a hydrogen atom, and R3 is a hydrogen atom or a methoxy group, or together represent a bond, or R3 is a hydrogen atom, R7 and R8 together represent a bond, R4 is an 01-C4 alkyl or 02-C4 alkenyl group, x is an oxygen or sulfur atom, and R5 is a hydrogen atom or a 01-C4 is an alkyl group, bR9 is a hydrogen atom, and B is a cyano group or a 02-C5 alkoxycarbonyl group, or R
9 and B together represent a group -C-W (in the formula, W is an oxygen atom or an imino group), A is 2〇H2, c
a2ca2 t: or 0H-OHi, and n is 0% 1 or 2.
Compounds or pharmaceutically acceptable salts thereof. 5) The compound according to claim 1 which is 6-methyl-8β-((IL3H)-2,4-dioxo-dihydro-1-pyrimidinyl-methylcouergoline or a pharmaceutically acceptable compound thereof) 4) The compound according to claim 1, which is 6-methy/L-8β-[2,4-dioxo-1:imidazolidinylmethyl]-ergoline, or a pharmaceutically acceptable salt thereof. . 5) 6-Methyl-8β-(N-(2-methoxycarbonylethyl)-N-carbamoyl-aminomethyltoergoline, 6-methyl-8β-(N-(2-methoxycarbonylethyl)-N-methyl Carbamoyl-aminomethyltuergoline, 6-methyl-8ρ-((in, 3H)-2,4-dioxo-3-methyl-dihydro-1-pyrimidinyl-methylcouergoline. 6-methyl-8β-[N -Ethoxycarbonylmethyl-
N-methylcarbamoyl-aminomethyltoergoline, 6-methyl8β-(2,4-dioxo-6-methyl-1
-imidazolidinyl-methyl)-ergoline, 6-methyl-8β-(N-(2-methoxycarbonylethyl) -N-furopyrucarbamoyl-aminomethyltoergoline, 6-methyl-8β-((IH,5H) -2,4-dioxo-3-propyl-dihydro-1-pyrimidinyl-methyltsundylgoline, 6-methyl-8β-(N-(2-methoxycarbonylethyl)-N-4soprovir-rubamoyl-aminomethyl]- Ergoline, 6-methyl-8β-((illps
a) -2t4-dioxo-6-inpropyl-dihydro-1-pyrimidinyl-methyl-two-helcholine. 6-if syl-β-(IJ-ethoxycarbonylmethyl-N--10 pylcarbamoyl-aminomethyltoergoline, 6-methyl8β-(2,4-dioxo-6-broby-1-imidazolidinyl-methyl)-ergoline , 6-methyl-8β-(N-ethoxycarbonylmethyl-
N-isopropylluca, lunokumoyl-aminomethyl)
-ergoline, 6-, methyl-8β-(2,4-dioxo-6-isopropyl-1-imidazolidinyl-methyl)-ergoline, 6-methyl-8β-(2-C(IH,3H) -2,4
-dioxo-dihydro-1-pyrimidinyl]-ethyl)
Ergoline, 6-methyl-8β-(2-(2,4-dioquine-1-imidazolidinyl)-ethylcouergoline, 6-methyl-8β-((IH,3H)-2,4-dioxo-dihydro-1 -pyrimidinyl]-ergoline
, 6-methyl-8β-(2,4-dioxo-1-imidazolidinyl)-ergoline, 1,6-dimethyl-8β-((1H,3H)-2,4-
Dioxo-dihydro-1-pyrimidinyl-methyltoergoline, 1,6-dimethyl-8β-(2,4-dioquine-1-imidazolidinyl-methyl)-ergoline, 6-methyl-
10-methoxy-8β-(2,4-dioxo-1-imidazolidi'nyl-methyl)-ergoline, 6-methyl-8β-(C1a, 6a)-2,4-dioxo-1-pyrimidinyl-methylionylgoline, 6- Methyl-8β-((1H)'-2-thioquine-4-oxo-tetrahydro-1-pyrimidinyl-methyltwoergoline, 6-methyl-8β-CC1H) -2-thioxo-4-
Oxo-6-methyl-tetrahydro-1-hyrimidinyl-methyl]-ergoline, 6-n-propyl-8β-[
: (IH) -2-thioxo-4-oxo-6-methyl-tetrahydro-1-pyrimidinyl-methyl]-ercoline, 6-allyl-8β-((IH) -2-thioxo-4-oxo-6 -Methyl-tetrahydro-1-hyrimidinyl-methyl]-ergoline, 6-methyl-8β-(
2-thioxo-4-oxo-6-methyl-1-imidazolidinyl-methyl)-ergoline, 6-broby-8β-(2-thioxo-4-oxo-6
-Methyl-1-imidazoly, dinylumethyl)-ergoline, 6-allyl-8β-(2-thioxo-4-oxo-6-
Methyl-1-imidazolidinyl-methyl)-ergoline, 6-methyl-8β-(N-(2-cyanoethyl)-N-
Carbamoyl-aminomethyl]-ergoline, 6-methyl-8β-((IH,3H)-2-oxo-4
-imino-dihydro-1-pyrimidinyl-methyltwoergoline 2-bromo-6-methyl-8β-(2,4-dioxo-
1-imidazolidini, rumethyl)-ergoline, 2,6-dimethyl-8β-(2,4-dioxo1-
imidazolidinyl-methyl)-ergoline, 2-thiomethyl-6-methyl-8β-(2,4-thioxo-1-imidazolidinyl-methyl)-ergoline, 6-n-propyl-8β-(2,4-dioxo-1-imidazolidinyl) -Methyl)-ergoline, 6-methyl-8α-(2,4-dioquine-1-imidazolidinyl-methyl)-ergoline, 6-methyl-8-(
(IH,3H)-2,4-dioxo-dihydro-1-pyrimidinyl-methylcy8,9-didehydroergoline, 6-methyl-8-(2,4-dioxo-1-imidazolidinyl-methyl) -8, 9-didehydro-ergoline, 6-methyl-8β-((IH,3H)-2,4-dioxo-dihydro-1-pyrimidinyl-methyl]-9,10
-didehydro-ergoline, or 6-methyl-8β-
(2,4-dioxo-1-imidazolidinyl-methyl)
-9,10-ditehydroergoline t or a pharmaceutically acceptable compound thereof. 6) Formula ■ (wherein R1, R2, R3, R4, R7, R8, A, B and n are as defined in claim 1)
2■ X=C! -=N=R5111 (wherein R5 and Compounds of formula I (wherein R9 is scale)'fr are cyclized to form other formula I (wherein B and R9 together represent a -a=W group, where W is A process for preparing a compound of formula I as defined in claim 1, comprising: 7) Process according to claim 5, characterized in that the condensation is carried out in water, ethanol, acetic acid or pyridine. 8) A method according to claim 6, wherein the combination is carried out at a temperature of 50 to 100°C. 9) A process according to any one of the preceding claims, characterized in that the cyclization is carried out in the same condensation medium. 10) Isolated nfc formula l (wherein R9 is hydrogen)
9. A method according to any one of the preceding claims, comprising cyclizing the compound having the following properties by heating it under vacuum to 130-160<0>C. 11) A pharmaceutical product consisting of a compound of formula I according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. composition. 12) consisting of the compound Fh having formula 1 according to any one of the preceding claims 1 to 5 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. Antihypertensive.